This invention relates to the field of synthesis of 14-hydroxymorphinans and more particularly to a novel and improved process for the preparation of noroxycodone, noroxymorphone and certain novel intermediates useful in such synthesis.
14-hydroxymorphinans, such as naloxone, naltrexone, and nalbuphine are important morphine derivatives due to their behavior as potent analgesics and/or narcotic antagonists. Prior to the instant invention, the most practical synthetic routes to the preparation of these pharmaceuticals have utilized thebaine as a starting material. Thus, in accordance with one conventional process, thebaine is oxidized to 14-hydroxycodeinone by use of m-chloroperbenozoic acid in an acetic acid/trifluoroacetic acid mixture or by a mixture of hydrogen peroxide and formic acid. 14-hydroxycodeinone is catalytically reduced to oxycodone that is in turn O-demethylated with boron tribromide to yield oxymorphone. After blocking of the hydroxyl groups with a suitable blocking agents such as acetyl groups, the oxymorphone derivative is reacted with cyanogen bromide to yield an N-cyanodihydronormorphinone derivative that is thereafter hydrolyzed to 14-hydroxydihydronormorphinone (noroxymorphone). Although the synthesis is effective, the availability of thebaine is limited and its cost high, thereby contributing to high cost of the noroxymorphone and the 14-hydroxymorphinans derived from it.
Because of the scarcity and high cost of thebaine, efforts have been made in the art to devise new methods for the synthesis of noroxymorphone and noroxycodone.
Because of their relatively low price and abundance, codeine and other 3-O-alkylmorphines are attractive and readily available potential precursors to noroxymorphone. The key transformation required for conversion of codeine to noroxymorphone is oxidation at the allylic position to provide the 14-hydroxy derivative. However, the direct allylic oxidation of codeine has met with only limited success and has generally been characterized by low yields. Thus, for example, attempts have been made to introduce the 14-hydroxy group by oxidation with chromic anhydride and sulfuric acid, with manganese dioxide, with selenium dioxide, and with t-butyl hydroperoxide. None of these efforts have produced 14-hydroxylated products in satisfactory yields. Other attempts have been made to synthesize thebaine from codeine or codeinone, thereby reducing the scarcity and cost of that intermediate, from which the 14-hydroxy compounds can be produced by known methods with relative efficiency.
There has, however, remained, an unfulfilled need in the art for novel and efficient methods for preparing noroxycodone and noroxymorphone from codeine.